SHARP Pathway Database



Institut Curie node:

     Coordinator: Patrick Poullet.

     Participants: Amélie Gelay, Andrei Zinovyev, Philippe La Rosa and Emmanuel Barillot.

     Collaborators: François Radvanyi, Olivier Delattre, Yohanns Bellaiche and Jean de-Gunzburg.

SHARP global coordinator: Ron Shamir (School of Computer Science, Tel Aviv University, Israel).


The SHARP project:

Making sense of the intricate network of proteins and genes regulations that take place inside the cell during cell growth, differentiation and apoptosis is a critical step in understanding how these processes are controlled at the molecular level. Unfortunately, the biological knowledge collected so far is fragmented in thousands of research articles of heterogeneous quality making it difficult for researchers to comprehend globally the mechanisms involved. This knowledge must be centralized and standardized to become easily accessible. Furthermore, as the data accumulate, it becomes necessary to use computer power to store, visualize and analyze these complex regulations.

The SHARP consortium was initiated by Ron Shamir at Tel Aviv University to address this problem using a collaborative approach. Researchers from all around the world -including from the Institut Curie- have already joined this consortium. The goal of this global collaboration is to take advantage of each research group’s expertise on specific signaling pathways to collect, curate and formalize the data available from the literature or from their own laboratories. New data are regularly integrated to a central pathway database and made available to all members of the consortium (see figure below).

A SHARP software was designed and developed by Ron Shamir’s group to assist researchers through this task. This tool consists of a multi-platform (java-based) intuitive pathway visualization module which communicates with an underlying database. The user can use this interface to submit new data and to query, edit and analyze the data stored. This tool can also be used to superimposed external quantitative data such as gene expression data (microarrays) over the signaling pathways.

Our task is to provide technical support to the research groups of the Institut Curie involved in the SHARP project and to coordinate their work with that of the other members of the consortium. The data collected are then used in other projects of the Group in particular for the analysis of microarray data (e.g. Kernelchip).



The Retinoblastoma (RB) Pathway case:

Participants: Amélie Gelay, François Radvanyi, Andrei Zinovyev, Emmanuel Barillot.


The purpose of the present work is to collect as much information as possible on gene-regulatory networks and organize it in an exploitable way for the analysis of data from microarrays. We started with RB, a tumor suppressor gene involved in a pathway controlling the cell cycle progression, which is one of the most frequent targets of genetic alterations in human cancer.

The data are collected from public sources (reviews, publications…) and stored using CellDesigner. CellDesigner is a structured diagram editor for drawing gene-regulatory and biochemical networks. These networks are drawn based on the process diagram, with the graphical notation system proposed by Kitano, and are stored using the Systems Biology Markup Language (SBML). SBML is a standard computer-readable format for representing models of biochemical reaction networks. It is applicable to metabolic networks, cell-signaling pathways, regulatory networks, and many others. Once converted in SBML format, signaling pathway data can be imported in network visualization tools such as SHARP.

View full-size image.

References for CellDesigner:

1.        Kitano, H., Funahashi, A., Matsuoka, Y., Oda, K. (2005) Using process diagrams for the graphical representation of biological networks. Nat Biotechnol. 23(8):961-6.

2.        Kitano, H. (2003) A graphical notation for biochemical networks. BIOSILICO. 1. 169-176.

3.        Hucka, M., Finney, A., Sauro, H.M., Bolouri, H., Doyle, J.C., Kitano, H., Arkin, A.P., Bornstein, B.J., Bray, D., Cornish-Bowden, A., Cuellar, A.A., Dronov, S., Gilles, E.D., Ginkel, M., Gor, V., Goryanin, I.I., Hedley, W.J., Hodgman, T.C., Hofmeyr, J.H., Hunter, P.J., Juty, N.S., Kasberger, J.L., Kremling, A., Kummer, U., Le Novere, N., Loew, L.M., Lucio, D., Mendes, P., Minch, E., Mjolsness, E.D., Nakayama, Y., Nelson, M.R., Nielsen, P.F., Sakurada, T., Schaff, J.C., Shapiro, B.E., Shimizu, T.S., Spence, H.D., Stelling, J., Takahashi, K., Tomita, M., Wagner, J., Wang, J.; SBML Forum. (2003) The systems biology markup language (SBML): a medium for representation and exchange of biochemical network models. Bioinformatics. 19(4):524-31

4.        Kitano, H. (2002) Systems biology: a brief overview. Science 295(5560):1662-4.


References for the Retinoblastoma pathway:

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2.         Attwooll, C., Oddi, S., Cartwright, P., Prosperini, E., Agger, K., Steensgaard, P., Wagener, C., Sardet, C., Moroni, M.C., Helin, K. (2005) A novel repressive E2F6 complex containing the polycomb group protein, EPC1, that interacts with EZH2 in a proliferation-specific manner. J Biol Chem. 280(2):1199-208.

3.         Bartkova, J., Horejsi, Z., Koed, K., Kramer, A., Tort, F., Zieger, K., Guldberg, P., Sehested, M., Nesland, J.M., Lukas, C., Orntoft, T., Lukas, J., Bartek, J. (2005) DNA damage response as a candidate anti-cancer barrier in early human tumorigenesis. Nature. 434(7035):864-70.

4.         Blais, A., Dynlacht, B.D. (2004) Hitting their targets: an emerging picture of E2F and cell cycle control. Curr Opin Genet Dev. 14(5):527-32.

5.         Boyer Arnold, N., Korc, M. (2005) Smad7 abrogates transforming growth factor-beta1-mediated growth inhibition in COLO-357 cells through functional inactivation of the retinoblastoma protein. J Biol Chem. 280(23):21858-66.

6.         Brehm, A., Miska, E.A., McCance, D.J., Reid, J.L., Bannister, A.J., Kouzarides, T. (1998) Retinoblastoma protein recruits histone deacetylase to repress transcription. Nature. 391(6667):597-601.

7.         Brown, VD., Phillips, R.A., Gallie, B.L. (1999) Cumulative effect of phosphorylation of pRB on regulation of E2F activity. Mol Cell Biol. 19(5):3246-56.

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23.      Fortin, A., MacLaurin, J.G., Arbour, N., Cregan, S.P., Kushwaha, N., Callaghan, S.M., Park, D.S., Albert, P.R., Slack, R.S. (2004) The proapoptotic gene SIVA is a direct transcriptional target for the tumor suppressors p53 and E2F1. J Biol Chem. 279(27):28706-14.

24.      Frolov, M.V., Dyson, N.J. (2004) Molecular mechanisms of E2F-dependent activation and pRB-mediated repression. J Cell Sci. 117(Pt 11):2173-81.

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35.      Knudsen, ES., Wang, J.Y. (1997) Dual mechanisms for the inhibition of E2F binding to RB by cyclin-dependent kinase-mediated RB phosphorylation. Mol Cell Biol. 17(10):5771-83.

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38.      Logan, N., Delavaine, L., Graham, A., Reilly, C., Wilson, J., Brummelkamp, T.R., Hijmans, E.M., Bernards, R., La Thangue, N.B. (2004) E2F-7: a distinctive E2F family member with an unusual organization of DNA-binding domains. Oncogene. 23(30):5138-50.

39.      Logan, N., Graham, A., Zhao, X., Fisher, R., Maiti, B., Leone, G., La Thangue, N.B. (2005) E2F-8: an E2F family member with a similar organization of DNA-binding domains to E2F-7. Oncogene. 24(31):5000-4.

40.      Ludlow, JW., Glendening, C.L., Livingston, D.M., DeCarprio, J.A. (1993) Specific enzymatic dephosphorylation of the retinoblastoma protein. Mol Cell Biol. 13(1):367-72.

41.      Lund, A.H., van Lohuizen, M. (2004) Polycomb complexes and silencing mechanisms. Curr Opin Cell Biol. 16(3):239-46.

42.      Magae, J., Wu, C.L., Illenye, S., Harlow, E., Heintz, N.H. (1996) Nuclear localization of DP and E2F transcription factors by heterodimeric partners and retinoblastoma protein family members. J Cell Sci. 109 (Pt7):1717-26.

43.      Magnaghi-Jaulin, L., Groisman, R., Naguibneva, I., Robin, P., Lorain, S., Le Villain, J.P., Troalen, F., Trouche, D., Harel-Bellan, A. (1998) Retinoblastoma protein represses transcription by recruiting a histone deacetylase. Nature. 391(6667):601-5.

44.      Maiti, B., Li, J., de Bruin, A., Gordon, F., Timmers, C., Opavsky, R., Patil, K., Tuttle, J., Cleghorn, W., Leone, G. (2005) Cloning and characterization of mouse E2F8, a novel mammalian E2F family member capable of blocking cellular proliferation. J Biol Chem. 280(18):18211-20.

45.      Muchardt, C., Yaniv, M. (2001) When the SWI/SNF complex remodels...the cell cycle. Oncogene. 20(24):3067-75.

46.      Muller, H., Bracken, A.P., Vernell, R., Moroni, M.C., Christians, F., Grassilli, E., Prosperini, E., Vigo, E., Oliner, J.D., Helin, K. (2001) E2Fs regulate the expression of genes involved in differentiation, development, proliferation, and apoptosis. Genes Dev. 15(3):267-85.

47.      Nevins, JR. (2001) The Rb/E2F pathway and cancer. Hum Mol Genet. 10(7):699-703.

48.      Nielsen, SJ., Schneider, R., Bauer, U.M., Bannister, A.J., Morrison, A., O'Carroll, D., Firestein, R., Cleary, M., Jenuwein, T., Herrera, R.E., Kouzarides, T. (2001) Rb targets histone H3 methylation and HP1 to promoters. Nature. 412(6846):561-5.

49.      Ogawa, H., Ishiguro, K., Gaubatz, S., Livingston, D.M., Nakatani, Y. (2002) A complex with chromatin modifiers that occupies E2F- and Myc-responsive genes in G0 cells. Science. 296(5570):1132-6.

50.      Parakati, R., DiMario, J.X. (2005) Dynamic transcriptional regulatory complexes, including E2F4, p107, p130, and Sp1, control fibroblast growth factor receptor 1 gene expression during myogenesis. J Biol Chem. 280(22):21284-94.

51.      Pohlers, M., Truss, M., Frede, U., Scholz, A., Strehle, M., Kuban, R.J., Hoffmann, B., Morkel, M., Birchmeier, C., Hagemeier, C. (2005) A role for E2F6 in the restriction of male-germ-cell-specific gene expression. Curr Biol. 15(11):1051-7.

52.      Polager, S., Kalma, Y., Berkovich, E., Ginsberg, D. (2002) E2Fs up-regulate expression of genes involved in DNA replication, DNA repair and mitosis. Oncogene. 21(3):437-46.

53.      Powers, J.T., Hong, S., Mayhew, C.N., Rogers, P.M., Knudsen, E.S., Johnson, D.G. (2004) E2F1 uses the ATM signaling pathway to induce p53 and Chk2 phosphorylation and apoptosis. Mol Cancer Res. 2(4):203-14.

54.      Rayman, JB., Takahashi, Y., Indjeian,V.B., Dannenberg, J.H., Catchpole, S., Watson, R.J., te Riele, H., Dynlacht, B.D. (2002) E2F mediates cell cycle-dependent transcriptional repression in vivo by recruitment of an HDAC1/mSin3B corepressor complex. Genes Dev. 16(8):933-47.

55.      Rogoff, H.A., Pickering, M.T., Frame, F.M., Debatis, M.E., Sanchez, Y., Jones, S., Kowalik, T.F. (2004) Apoptosis associated with deregulated E2F activity is dependent on E2F1 and Atm/Nbs1/Chk2. Mol Cell Biol. 24(7):2968-77.

56.      Salomoni, P., Pandolfi, P.P. (2002) The role of PML in tumor suppression. Cell. 108(2):165-70.

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61.      Stevens, C., Smith, L., La Thangue, N.B. (2003) Chk2 activates E2F-1 in response to DNA damage. Nat Cell Biol. 5(5):401-9.

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